Montelukast, a CysLT1 receptor antagonist, reduces colon cancer stemness and tumor burden in a mouse xenograft model of human colon cancer.

Abstract

Inflammation is implicated in the etiology of sporadic colon cancer (CC), which is one of the leading causes of cancer-related deaths worldwide. Here, we report that inhibition of the inflammatory receptor CysLT1 through its antagonist, montelukast, is beneficial in minimizing stemness in CC and thereby minimizing tumor growth in a mouse xenograft model of human colon cancer. Upon treatment with montelukast, colonospheres derived from HT-29 and SW-480 human colon cancer cells exhibited a significant phenotypic change coupled with the downregulation of mRNA and protein expression of cancer stem cell (CSC) markers ALDH1 and DCLK1. Moreover, montelukast reduced the size of HT-29 cell-derived tumors in mice. The reduction in tumor size was associated with decreased levels of ALDH1A1, DCLK1, BCL2 mRNA and macrophage infiltration into the tumor tissue. Interestingly, this treatment elevated levels of the tumor suppressor 15-PGDH while reducing COX-2 expression. Our data highlight the association of CysLT1R with CSCs and demonstrate that inhibition of CysLT1R could prove beneficial in minimizing CSC-induced tumor growth. This work advances the notion that targeting CSCs is a promising approach to improve outcomes in those afflicted with colon cancer.

• Authors: Kishan Bellamkonda, Shakti Ranjan Satapathy, Desiree Douglas, Naveenkumar Chandrashekar, Benson Chellakkan Selvanesan, Minghui Liu, Sayeh Savari, Gunilla Jonsson, Anita Sjölander
• Journal: Cancer letters (Cancer Lett) Vol. 437 Pg. 13-24 (11 28 2018) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 30144515 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Acetates
• Cyclopropanes
• Leukotriene Antagonists
• Quinolines
• Receptors, Leukotriene
• Sulfides
• leukotriene D4 receptor
• montelukast

Topics

• Acetates (pharmacology)
• Animals
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, genetics, metabolism)
• Cyclopropanes
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HT29 Cells
• Humans
• Leukotriene Antagonists (pharmacology)
• Mice, Inbred BALB C
• Mice, Nude
• Neoplastic Stem Cells (drug effects, metabolism)
• Quinolines (pharmacology)
• Receptors, Leukotriene (genetics, metabolism)
• Sulfides
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays (methods)